Crystalline forms of pitavastatin calcium

ABSTRACT

The present invention is directed to new crystalline forms of Pitavastatin hemicalcium salt, referred to hereinafter as polymorphic Forms A, B, C, D, E and F, as well as the amorphous form. Furthermore, the present invention is directed to processes for the preparation of these crystalline forms and the amorphous form and pharmaceutical compositions comprising these crystalline forms or the amorphous form.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/331,086, filed on Dec. 9, 2008, which is a continuation of U.S.patent application Ser. No. 10/544,752, filed on Aug. 8, 2005, which wasa 371 of International Patent Application No. PCT/EP2004/050066, filedon Feb. 2, 2004, and claims priority to European Patent Application No.03405080.7, filed on Feb. 12, 2003, all of which are incorporated hereinby reference in their entireties.

The present invention is directed to new crystalline forms and theamorphous form of Pitavastatin calcium, processes for the preparationthereof and pharmaceutical compositions comprising these forms.

The present invention relates to new crystalline forms and the amorphousform of Pitavastatin calcium. Pitavastatin is also known by the namesNK-104, Itavastatin and Nisvastatin. Pitavastatin calcium is known bythe chemical name:(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid hemicalcium salt. Pitavastatin calcium has the following formula:

Pitavastatin calcium has recently been developed as a new chemicallysynthesized and powerful statin by Kowa Company Ltd, Japan. On the basisof reported data, the potency of Pitavastatin is dose-dependent andappears to be equivalent to that of Atorvastatin. This new statin issafe and well tolerated in the treatment of patients withhypercholesterolaemia. Significant interactions with a number of othercommonly used drugs can be considered to be extremely low.

Processes for the preparation of Pitavastatin are described inEP-A-0304063 and EP-A-1099694 and in the publications by N. Miyachi etal. in Tetrahedron Letters (1993) vol. 34, pages 8267-8270 and by K.Takahashi et al. in Bull. Chem. Soc. Jpn. (1995) vol. 68, 2649-2656.These publications describe the synthesis of Pitavastatin in greatdetail but do not describe the hemicalcium salt of Pitavastatin. Thepublications by L. A. Sorbera et al. in Drugs of the Future (1998) vol.23, pages 847-859 and by M. Suzuki et al. in Bioorganic & MedicinalChemistry Letters (1999) vol. 9, pages 2977-2982 describe Pitavastatincalcium, however, a precise procedure for its preparation is not given.A full synthetic procedure for the preparation of Pitavastatin calciumis described in EP-A-0520406. In the process described in this patentPitavastatin calcium is obtained by precipitation from an aqueoussolution as a white crystalline material with a melting point of 190-192C. It is known that pharmaceutical substances can exhibit polymorphism.Polymorphism is commonly defined as the ability of any substance to havetwo or more different crystal structures. Drug substances may alsoencapsulate solvent molecules when crystallized. These solvates orhydrates are referred to as pseudopolymorphs. It is also possible thatthe amorphous form is encountered. Different polymorphs,pseudopolymorphs or the amorphous form differ in their physicalproperties such as melting point, solubility etc. These can appreciablyinfluence pharmaceutical properties such as dissolution rate andbioavailability. It is also economically desirable that the product isstable for extended periods of time without the need for specializedstorage conditions. It is therefore important to evaluate polymorphismof drug substances. Furthermore, the discovery of new crystallinepolymorphic forms of a drug enlarge the repertoire of materials that aformulation scientist has with which to design a pharmaceutical dosageform of a drug with a targeted release profile or other desiredcharacteristics. We now have surprisingly found novel crystalline formsof Pitavastatin calcium, herein designated as form A, B, C, D, E and F,and the amorphous form of Pitavastatin calcium.

Accordingly, the present invention is directed to the polymorphic FormsA, B, C, D, E and F, and the amorphous form of Pitavastatin calcium salt(2:1).

One object of the invention is a crystalline polymorph of(3R,5S)-7-12-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid hemicalcium salt, herein designated as Form A, which exhibits acharacteristic X-ray powder diffraction pattern with characteristicpeaks expressed in d-values (Å) and in 2θ as given in Table 1 (vs=verystrong intensity, s=strong intensity, m=medium intensity, w=weakintensity, vw=very weak intensity).

TABLE 1 d-spacings and 2θ angles for Form A. d-spacing [Å] Angle [2θ]Rel. Intensity 17.6   5.0 s 13.0   6.8 s 9.7  9.1 s 8.8 10.0 w 8.4 10.5m 8.1 11.0 m 6.7 13.3 vw 6.5 13.7 s 6.3 14.0 w 6.0 14.7 w  5.57 15.9 vw 5.25 16.9 w  5.17 17.1 vw  4.82 18.4 m  4.64 19.1 w  4.27 20.8 vs  4.2021.1 m  4.10 21.6 m  3.87 22.9 m  3.74 23.7 m  3.67 24.2 s  3.53 25.2 w 3.29 27.1 m  3.02 29.6 vw  2.95 30.2 w  2.63 34.0 w

Another object of the invention is a crystalline polymorph of(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid hemicalcium salt, herein designated as Form B, which exhibits acharacteristic X-ray powder diffraction pattern with characteristicpeaks expressed in d-values (Å) and in 2θ as given in Table 2.

TABLE 2 d-spacings and 2θ angles for Form B. d-spacing [Å] Angle [2θ]Rel. Intensity 19.0  4.6 w 16.6  5.3 vs 14.2  6.2 s 11.5  7.7 s  9.6 9.2 m  9.2  9.6 m  8.5 10.3 w  7.8 11.3 m  7.6 11.7 w  7.0 12.6 vw  6.813.0 w  6.4 13.9 m  6.0 14.7 vw 5.94 14.9 w 5.66 15.6 w 5.43 16.3 m 5.2217.0 vw 5.10 17.4 vw 4.92 18.0 w 4.74 18.7 m 4.59 19.3 m 4.43 20.0 s4.33 20.5 w 4.26 20.8 m 4.19 21.2 w, shoulder 4.13 21.5 m 3.97 22.4 m3.83 23.2 s 3.73 23.6 m 3.64 24.4 vw 3.53 25.2 w, broad 3.42 26.0 w 3.3726.4 vw 3.30 27.0 w 3.19 27.9 vw 3.09 28.9 w

Another object of the invention is a crystalline polymorph of(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid hemicalcium salt, herein designated as Form C, which exhibits acharacteristic X-ray powder diffraction pattern with characteristicpeaks expressed in d-values (Å) and in 2θ as given in Table 3.

TABLE 3 d-spacings and 2θ angles for Form C. d-spacing [Å] Angle [2θ]Rel. Intensity 21.6   4.1 m 15.9   5.6 s 11.4   7.8 m 10.6   8.3 m 8.6 10.3 m 7.7  11.6 w 5.06 17.5 w 4.95 17.9 w 4.74 18.7 m 4.55 19.5 s 4.3120.6 m 4.13 21.5 vw 4.06 21.9 m 3.84 23.1 m 3.71 24.0 w 3.58 24.8 w

Another object of the invention is a crystalline polymorph of(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid hemicalcium salt, herein designated as Form D, which exhibits acharacteristic X-ray powder diffraction pattern with characteristicpeaks expressed in d-values (Å) and in 2θ as given in Table 4.

TABLE 4 d-spacings and 2θ angles for Form D. d-spacing [Å] Angle [2θ]Rel. Intensity 17.5   5.0 m 13.5   6.5 m 13.0   6.8 s 10.1   8.7 m 8.8 10.0 m 8.6  10.2 m 8.2  10.8 m 6.8  13.1 w 6.55 13.5 m 6.20 14.3 s 5.7815.3 vw 5.52 16.1 m 5.28 16.8 w 4.87 18.2 w 4.80 18.5 m 4.66 19.0 w 4.4619.9 m 4.34 20.5 m 4.23 21.0 vs 4.09 21.7 s 3.99 22.3 w 3.80 23.4 m 3.7024.0 m 3.47 25.6 w 3.40 26.2 m

Another object of the invention is a crystalline polymorph of(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid hemicalcium salt, herein designated as Form E, which exhibits acharacteristic X-ray powder diffraction pattern with characteristicpeaks expressed in d-values (Å) and in 2θ as given in Table 5.

TABLE 5 d-spacings and 2θ angles for Form E. d-spacing [Å] Angle [2θ]Rel. Intensity 20.0  4.4 vw 17.7  5.0 s 13.4  6.6 s 13.1  6.8 s 10.0 8.9 s  8.8 10.0 m  8.6 10.3 s  8.2 10.8 m  6.6 13.3 s  6.5 13.6 m  6.314.0 s 5.84 15.2 vw 5.56 15.9 w 5.39 16.4 w 5.24 16.9 vw 4.99 17.8 vw4.84 18.3 m 4.69 18.9 w 4.39 20.2 vs 4.34 20.4 m 4.30 20.7 m 4.24 20.9 m4.21 21.1 vs 4.12 21.6 m 4.08 21.7 m 3.99 22.3 m 3.77 23.5 m 3.73 23.8 m3.69 24.1 w 3.60 24.7 vw 3.50 25.4 vw 3.35 26.6 m 2.96 30.2 w 2.64 34.0vw

Another object of the invention is a crystalline polymorph of(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid hemicalcium salt, herein designated as Form F, which exhibits acharacteristic X-ray powder diffraction pattern with characteristicpeaks expressed in d-values (Å) and in 2θ as given in Table 6.

TABLE 6 d-spacing and 2θ angles for Form F. d-spacing [Å] Angle [2θ]Rel. Intensity 17.2   5.1 m 15.8   5.6 w 12.6   7.0 s 10.0   8.8 m 9.2  9.6 s 8.7  10.2 w 8.1  10.9 m 7.8  11.3 w 7.4  11.9 m 7.1  12.5 m 6.8 13.0 s 6.5  13.7 m 6.2  14.4 s 8.04 14.7 m 5.79 15.3 vw 5.70 15.5 w 5.2816.8 m 5.03 17.6 w 4.85 18.3 m 4.61 19.3 m 4.51 19.7 m 4.30 20.6 m 4.1821.2 vs 4.08 21.8 s 3.90 22.8 s 3.84 23.1 w 3.74 23.8 w, shoulder 3.6924.1 s 3.59 24.8 s 3.46 25.7 m 3.40 26.2 vw 3.35 26.6 m 3.31 26.9 w 3.1428.4 w 3.02 29.5 w 3.00 29.8 vw 2.89 30.9 m

Small changes in the experimental details can cause small deviation inthe d-values and 2θ of characteristic peaks in the X-ray powderdiffraction patterns.

Another object of the invention is the amorphous form of(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid hemicalcium salt which exhibits characteristic X-ray powderdiffraction patterns as depicted in FIG. 7.

Powder X-ray diffraction is performed on a Philips 1710 powder X-raydiffractometer using Cu k (α1) radiation (1.54060 Å); 2θ angles arerecorded with an experimental error of ±0.1-0.2°. A discussion of thetheory of X-ray powder diffraction patterns can be found in “X-raydiffraction procedures” by H. P. Klug and L. E. Alexander, J. Wiley, NewYork (1974).

Furthermore, the present invention is directed to processes for thepreparation of Form A, B, C, D, E and F, and the amorphous form ofPitavastatin calcium.

Form A can be generally prepared from Pitavastatin sodium upon reactionwith CaCl₂ in an aqueous reaction medium. Alternatively, Form A of theinvention may also be obtained in situ from the free acid((3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid) or the corresponding lactone with Ca(OH)₂, advantageously also inan aqueous reaction medium. The aqueous reaction medium usually containsat least 80% b.w. of water; preferably it is water or water containingminor amounts of solvents and/or reactants from previous steps. Form Amay contain up to 15% water, preferably about 3 to 12%, more preferably9 to 11% of water.

Form B can be generally prepared by suspending form A in ethanolcontaining water as a co solvent. The amount of water is preferablyabout 1 to 50%.

Form C can be generally prepared by suspending form A in isopropanolcontaining water as a co solvent. The amount of water is preferablyabout 1 to 50%, especially 1 to 20% and more preferably about 5%. Form Ccan also be prepared from a mixture of isopropanol and a ketone solvent,containing water as a co solvent. Preferably, the ketone solvent isacetone, and the amount of ketone solvent are about 1 to 30%, morepreferably about 10%. The amount of water is preferably about 1 to 20%,more preferably about 5%.

Form D can be generally prepared by suspending form A in absoluteethanol.

Form E can be generally prepared by suspending form A in 1,4-dioxanecontaining water as a co solvent. The amount of water is preferablyabout 1 to 50%.

Form F can be generally prepared by suspending form A in methanolcontaining water as a co solvent. The amount of water is preferablyabout 1 to 50%.

In the above mentioned processes small amounts of seeding crystals ofthe desired crystalline form may be added to the reaction mixture.Preferably small amounts are about 1 to 20 weight %, more preferablyabout 5 weight %. Seeding crystals may be added before or, whereappropriate, after the step initiating the crystallization (e.g.cooling, addition of non-solvent etc. as described above). Additionbefore initiating the crystallization is of specific technical interest.

The amorphous form can be generally prepared by addition of anon-solvent to a concentrated solution of Pitavastatin calcium in anorganic solvent. As non-solvent may be taken for example heptane ormethyl tert-butyl ether, whereas examples for the organic solvent are1,4-dioxane, tetrahydrofuran and ethyl methyl ketone. It is preferablethat the non-solvent and solvent are miscible. The amorphous form canalso be prepared by lyophilization of an aqueous solution ofPitavastatin calcium.

Preparations of polymorphic forms A, B, C, D, E, F as well as theamorphous form are usually done in substantially pure reaction systems,essentially consisting of the educt specified, preferably insubstantially crystalline form, and solvents and/or non-solvents asgiven above.

Another object of the present invention are processes for thepreparation of crystalline forms of Pitavastatin calcium essentiallyfree of residual organic solvent.

Particularly, the present invention is related to processes for thepreparation of crystalline forms of Pitavastatin calcium essentiallyfree of residual organic solvent by exposing the crystalline form ofPitavastatin calcium to an atmosphere with a defined relative airhumidity. More particularly, the present invention is directed to aprocess for the preparation of any crystalline form or amorphous form ofPitavastatin calcium which is essentially free of residual organicsolvent. These can, for example, be prepared by exposing the crystallineform or amorphous form to an atmosphere with a relative air humidity of5 to 100%. Preferably, these are prepared by exposure to an inert gasstream with a defined relative air humidity to exchange residual organicsolvent with water. In general, a relative air humidity of 5 to 100%,especially 40 to 80%, is used.

Another object of the present invention are pharmaceutical compositionscomprising an effective amount of crystalline polymorphic Form A, B, C,D, E or F or the amorphous form of Pitavastatin calcium, and apharmaceutical acceptable carrier.

These polymorphic forms may be used as single component or as mixtureswith other crystalline forms or the amorphous form.

As to the novel polymorphic forms and amorphous form of Pitavastatincalcium it is preferred that these contain 25-100% by weight, especially50-100% by weight, of at least one of the novel forms, based on thetotal amount of Pitavastatin calcium. Preferably, such an amount of thenovel polymorphic forms or amorphous form of Pitavastatin calcium is75-100% by weight, especially 90-100% by weight. Highly preferred is anamount of 95-100% by weight.

The compositions of the invention include powders, granulates,aggregates and other solid compositions comprising at least one of thenovel forms. In addition, the compositions that are contemplated by thepresent invention may further include diluents, such ascellulose-derived materials like powdered cellulose, microcrystallinecellulose, microfine cellulose, methyl cellulose, ethyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, carboxymethyl, cellulose salts and other substituted andunsubstituted celluloses; starch; pregelatinized starch; inorganicdiluents like calcium carbonate and calcium diphosphate and otherdiluents known to the pharmaceutical industry. Yet other suitablediluents include waxes, sugars and sugar alcohols like mannitol andsorbitol, acrylate polymers and copolymers, as well as pectin, dextrinand gelatin.

Further excipients that are within the contemplation of the presentinvention include binders, such as acacia gum, pregelatinized starch,sodium alginate, glucose and other binders used in wet and drygranulation and direct compression tableting processes. Excipients thatalso may be present in the solid compositions further includedisintegrants like sodium starch glycolat, crospovidone, low-substitutedhydroxypropyl cellulose and others. In addition, excipients may includetableting lubricants like magnesium and calcium stearate and sodiumstearyl fumarate; flavorings; sweeteners; preservatives;pharmaceutically acceptable dyes and glidants such as silicon dioxide.

The dosages include dosages suitable for oral, buccal, rectal,parenteral (including subcutaneous, intramuscular, and intravenous),inhalant and ophthalmic administration. Although the most suitable routein any given case will depend on the nature and severity of thecondition being treated, the most preferred route of the presentinvention is oral. The dosages may be conveniently presented in unitdosage form and prepared by any of the methods well-known in the art ofpharmacy.

Dosage forms include solid dosage forms, like tablets, powders,capsules, suppositories, sachets, troches and losenges as well as liquidsuspensions and elixirs. While the description is not intended to belimiting, the invention is also not intended to pertain to truesolutions of Pitavastatin calcium whereupon the properties thatdistinguish the solid forms of Pitavastatin calcium are lost. However,the use of the novel forms to prepare such solutions is considered to bewithin the contemplation of the invention.

Capsule dosages, of course, will contain the solid composition within acapsule which may be made of gelatin or other conventional encapsulatingmaterial. Tablets and powders may be coated. Tablets and powders may becoated with an enteric coating. The enteric coated powder forms may havecoatings comprising phthalic acid cellulose acetate,hydroxypropylmethyl-cellulose phthalate, polyvinyl alcohol phthalate,carboxymethylethylcellulose, a copolymer of styrene and maleic acid, acopolymer of methacrylic acid and methyl methacrylate, and likematerials, and if desired, they may be employed with suitableplasticizers and/or extending agents. A coated tablet may have a coatingon the surface of the tablet or may be a tablet comprising a powder orgranules with an enteric-coating.

Preferred unit dosages of the pharmaceutical compositions of thisinvention typically contain from 0.5 to 100 mg of the novel Pitavastatincalcium forms or mixtures thereof with each other or other forms ofPitavastatin calcium. More usually, the combined weight of thePitavastatin calcium forms of a unit dosage are from 2.5 mg to 80 mg,for example 5, 10, 20 or 40 mg.

The following Examples illustrate the invention in more detail.Temperatures are given in degrees Celsius.

EXAMPLE 1 Preparation of Form A

4.15 gr of(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid tert-butyl ester (Pitavastatin tert-butyl ester) was suspended in52 ml of a mixture of methyl tert-butyl ether and methanol (10:3). Tothis mixture were added 2.17 ml of a 4M aqueous solution of NaOH, andthe resulting yellowish solution was stirred for 2.5 hours at 50° C. Thereaction mixture was cooled to room temperature followed by the additionof 50 ml water and stirring for an additional hour. The aqueous phasewas separated and once extracted with 20 ml of methyl tert-butyl ether.To this aqueous solution were added a solution of 0.58 gr CaCl₂ in 80 mlof water over a period of 1 hour. The resulting suspension was stirredfor about 16 hours at room temperature. The suspension was filtered andthe obtained solid was dried at 40° C. and 50 mbar for about 16 hours.The obtained product is crystal Form A which is characterized by anX-ray powder diffraction pattern as shown in FIG. 1. Furthercharacterization of the obtained Form A by thermogravimetry coupled withFT-IR spectroscopy revealed a water content of about 10%. Differentialscanning calorimetry revealed a melting point of 95° C.

EXAMPLE 2 Preparation of Form B

100 mg Pitavastatin calcium Form A was suspended in 2 ml water andstirred at room temperature for 30 min, followed by the addition of 2 mlof ethanol and additional stirring for 18 hours. The suspension wasfiltered and dried in air, yielding 36 mg of Form B. The obtainedcrystal Form B is characterized by an X-ray powder diffraction patternas shown in FIG. 2. Further characterization of the obtained Form B bythermogravimetry coupled with FT-IR spectroscopy revealed a watercontent of about 10%.

EXAMPLE 3 Preparation of Form C

62 mg Pitavastatin calcium Form A was suspended in 2 ml isopropanolcontaining 5% water. This suspension was heated to 60° C., which led toalmost complete dissolution of Form A, and again cooled to roomtemperature. At this temperature the suspension was stirred for 66hours. The resulting suspension was filtered, once washed with someisopropanol containing 5% water, and dried in air. The obtained crystalForm C is characterized by an X-ray powder diffraction pattern as shownin FIG. 3. Further characterization of the obtained Form C bythermogravimetry coupled with FT-IR spectroscopy revealed that thesample contains about 6.3% isopropanol and a small amount of water.

EXAMPLE 4 Preparation of Form C

65 mg Pitavastatin calcium Form A was suspended in a mixture of 0.9 mlisopropanol, 0.1 ml acetone and 40 μl water. Stirring this suspensionfor about 1 hour led to nearly complete dissolution. Seeding with 4 mgof Form C (from example 3) and stirring for 2 hours led to the formationof a concentrated suspension. This suspension was diluted with the sameamount of solvent mixture as above and stirred for an additional 40hours. The suspension was filtered and the obtained solid was dried at40° C. for about 10 min. Analysis by X-ray powder diffraction indicatesthe product to be crystal Form C as shown in FIG. 3.

EXAMPLE 5 Preparation of Form D

60 mg of Pitavastatin calcium Form A was suspended in 1 ml absoluteethanol and stirred at room temperature for 20 hours. The resultingsuspension was filtered and dried in air. The obtained crystal Form D ischaracterized by an X-ray powder diffraction pattern as shown in FIG. 4.

EXAMPLE 6 Preparation of Form E

60 mg of Pitavastatin calcium Form A was suspended in a mixture of1,4-dioxane and water (1:1), and stirred for 18 hours at roomtemperature. The resulting suspension was filtered and dried in air. Theobtained crystal Form E is characterized by an X-ray powder diffractionpattern as shown in FIG. 5.

EXAMPLE 7 Preparation of Form F

60 mg of Pitavastatin calcium Form A was suspended in 3 ml methanolcontaining 20% water, and stirred at 40° C. for 1 hour. The resultingsuspension was slowly cooled to room temperature and stirring wascontinued for 4 hours. The suspension was heated again to 40° C.,stirred for 30 min, slowly cooled to room temperature and stirred for anadditionally 15 hours. The suspension was filtered and the obtainedwhite solid dried in air. The obtained crystal Form F is characterizedby an X-ray powder diffraction pattern as shown in FIG. 6.

EXAMPLE 8 Preparation of the Amorphous Form

-   -   -   -   -   62 mg of Pitavastatin calcium Form A was dissolved                    in 0.3 ml 1,4-dioxane. To this stirred solution was                    slowly added 2.3 ml n-heptane at room temperature,                    and stirred for an additional 16 hours. The                    resulting suspension was filtered and dried in air.                    The obtained solid was amorphous as is shown by the                    X-ray diffraction pattern given in FIG. 7 (top).

EXAMPLE 9 Preparation of the Amorphous Form

-   -   -   -   -   60 mg of Pitavastatin calcium Form A was dissolved                    in 1.5 ml ethyl methyl ketone. To this solution was                    added in steps of 1 ml each 30 sec a total of 21 ml                    methyl tert-butyl ether. The resulting suspension                    was stirred at room temperature for about 16 hours.                    The suspension was filtered and the obtained solid                    was dried in air. An X-ray diffraction study on the                    product showed it to be amorphous, see FIG. 7                    (bottom). Further characterization of the obtained                    product by thermogravimetry coupled with FT-IR                    spectroscopy revealed that the sample contained                    about 5.5% methyl tert-butyl ether. Differential                    scanning calorimetry showed the sample to have a                    glass transition temperature of about 68° C.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a characteristic X-ray powder diffraction pattern for Form A.

FIG. 2 is a characteristic X-ray powder diffraction pattern for Form B.

FIGS. 3A and 3B are two characteristic X-ray powder diffraction patternsfor Form C.

FIG. 4 is a characteristic X-ray powder diffraction pattern for Form D.

FIG. 5 is a characteristic X-ray powder diffraction pattern for Form E.

FIG. 6 is a characteristic X-ray powder diffraction pattern for Form F.

FIGS. 7A and 7B are two characteristic X-ray powder diffraction patternsfor the amorphous form.

1-14. (canceled)
 15. A process for the preparation of a crystallinepolymorph A according to claim 39, which comprises the reaction of(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid sodium salt with CaCl₂ in an aqueous reaction medium, or thereaction of the free acid(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid or the corresponding lactone with Ca(OH)₂.
 16. A process for thepreparation of crystalline polymorph B according to claim 39, whichcomprises suspending crystalline polymorph A according to claim 39 inethanol containing water as a cosolvent.
 17. A process according toclaim 16, wherein the amount of water is 1 to 50% by volume of thesuspension of(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-(E)-heptanoicacid hemicalcium salt.
 18. A process for the preparation of acrystalline polymorph C according to claim 39, which comprisessuspending crystalline polymorph A according to claim 39 in isopropanolcontaining water as a cosolvent.
 19. A process according to claim 18,wherein the amount of water is 1 to 50% by volume of the suspension of(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid hemicalcium salt.
 20. A process for the preparation of crystallinepolymorph C according to claim 39, which comprises suspendingcrystalline polymorph A according to claim 39 in a mixture ofisopropanol and a ketone solvent, containing water as a cosolvent.
 21. Aprocess according to claim 20 in which the ketone solvent is acetone.22. A process according to claim 20, wherein the amount of ketonesolvent is 1 to 30% by volume of the suspension of(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid hemicalcium salt.
 23. A process according to claim 20, wherein theamount of water is 1 to 20% by volume of the suspension of(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid hemicalcium salt.
 24. A process for the preparation of crystallinepolymorph D according to claim 39, which comprises suspendingcrystalline polymorph A according to claim 39 in absolute ethanol.
 25. Aprocess for the preparation of crystalline polymorph E according toclaim 39, which comprises suspending crystalline polymorph A accordingto claim 39 in 1,4-dioxane containing water as a cosolvent.
 26. Aprocess according to claim 25, wherein the amount of water is 1 to 50%by volume of the suspension of(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid hemicalcium salt.
 27. A process for the preparation of crystallinepolymorph E according to claim 39, which comprises suspendingcrystalline polymorph A according to claim 39 in methanol containingwater as a cosolvent.
 28. A process according to claim 27, wherein theamount of water is 1 to 50% by volume of the suspension of(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid hemicalcium salt.
 29. A process according to claim 15, wherein(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid hemicalcium salt is isolated by filtration and dried in air orvacuum.
 30. A process according to claim 15, wherein seeding is carriedout with crystals of the desired crystalline polymorph.
 31. A processfor the preparation of the amorphous form according claim 39, wherein anon-solvent is added to a solution of(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid hemicalcium salt in an organic solvent.
 32. A process according toclaim 31, wherein the non-solvent is selected from heptane and methyltert-butyl ether.
 33. A process according to claim 31, wherein theorganic solvent is selected from 1,4-dioxane, tetrahydrofuran and ethylmethyl ketone.
 34. A process for the preparation for the amorphous formaccording claim 39, wherein an aqueous solution of(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid hemicalcium salt is dried by lyophilization.
 35. A process for thepreparation of crystalline form A, B, C, D, E, F, or the amorphous formof(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid hemicalcium salt according to claim 39 essentially free of residualorganic solvents by exposing this crystalline form or amorphous form toan atmosphere with a relative air humidity of 5 to 100%.
 36. A processfor the preparation of a crystalline form A, B, C, D, E, F, or theamorphous form of(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid hemicalcium salt according to claim 39 essentially free of residualorganic solvents by equilibrating this crystalline form or amorphousform in an inert gas flow with a relative air humidity of 5 to 100%. 37.A process according to claim 31 in which the relative air humidity is 40to 80%.
 38. A pharmaceutical composition comprising an effective amountof a crystalline polymorphic form according to claim 39, and apharmaceutically acceptable carrier.
 39. A crystalline polymorph A, B,C, D, E, F, or the amorphous form, of(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid hemicalcium salt wherein A) polymorph A exhibits a characteristicX-ray powder diffraction pattern with characteristic peaks expressed in2θ at 5.0 (s), 6.8 (s), 9.1 (s), 10.0 (w), 10.5 (m), 11.0 (m), 13.3(vw), 13.7 (s), 14.0 (w), 14.7 (w), 15.9 (vw), 16.9 (w), 17.1 (vw), 18.4(m), 19.1 (w), 20.8 (vs), 21.1 (m), 21.6 (m), 22.9 (m), 23.7 (m), 24.2(s), 25.2 (w), 27.1 (m), 29.6 (vw), 30.2 (w), 34.0 (w); B) polymorph Bexhibits a characteristic X-ray powder diffraction pattern withcharacteristic peaks expressed in 2θ at 4.6 (w), 5.3 (vs), 6.2 (s), 7.7(s), 9.2 (m), 9.6 (m), 10.3 (w), 11.3 (m), 11.7 (w), 12.6 (vw), 13.0(w), 13.9 (m), 14.7 (vw), 14.9 (w), 15.6 (w), 16.3 (m), 17.0 (vw), 17.4(vw), 18.0 (w), 18.7 (m), 19.3 (m), 20.0 (s), 20.5 (w), 20.8 (m), 21.2(w, shoulder), 21.5 (m), 22.4 (m), 23.2 (s), 23.8 (m), 24.4 (vw), 25.2(w, broad), 26.0 (w), 26.4 (vw), 27.0 (w), 27.9 (vw), 28.9 (w); C)polymorph C exhibits a characteristic X-ray powder diffraction patternwith characteristic peaks expressed in 2θ at 4.1 (m), 5.6 (s), 7.8 (m),8.3 (m), 10.3 (m), 11.6 (w), 17.5 (w), 17.9 (w), 18.7 (m), 19.5 (s),20.6 (m), 21.5 (vw), 21.9 (m), 23.1 (m), 24.0 (w), 24.8 (w); D)polymorph D exhibits a characteristic X-ray powder diffraction patternwith characteristic peaks expressed in 2θ at 5.0 (m), 6.5 (m), 6.8 (s),8.7 (m), 10.0 (m), 10.2 (m), 10.8 (m), 13.1 (w), 13.5 (m), 14.3 (s),15.3 (vw), 16.1 (m), 16.8 (w), 18.2 (w), 18.5 (m), 19.0 (w), 19.9 (m),20.5 (m), 21.0 (vs), 21.7 (s), 22.3 (w), 23.4 (m), 24.0 (m), 25.6 (w),26.2 (m); E) polymorph E exhibits a characteristic X-ray powderdiffraction pattern with characteristic peaks expressed in 20 at 4.4(vw), 5.0 (s), 6.6 (s), 6.8 (s), 8.9 (s), 10.0 (m), 10.3 (s), 10.8 (m),13.3 (s), 13.6 (m), 14.0 (s), 15.2 (vw), 15.9 (w), 16.4 (w), 16.9 (vw),17.8 (vw), 18.3 (m), 18.9 (w), 20.2 (vs), 20.4 (m), 20.7 (m), 20.9 (m),21.1 (vs), 21.6 (m), 21.7 (m), 22.3 (m), 23.5 (m), 23.8 (m), 24.1 (w),24.7 (vw), 25.4 (vw), 26.6 (m), 30.2 (w), 34.0 (vw); and F) polymorph Fexhibits a characteristic X-ray powder diffraction pattern withcharacteristic peaks expressed in 2θ at 5.1 (m), 5.6 (w), 7.0 (s), 8.8(m), 9.6 (s), 10.2 (w), 10.9 (m), 11.3 (w), 11.9 (m), 12.5 (m), 13.0(s), 13.7 (m), 14.4 (s), 14.7 (m), 15.3 (vw), 15.5 (w), 16.8 (m), 17.6(w), 18.3 (m), 19.3 (m), 19.7 (m), 20.6 (m), 21.2 (vs), 21.8 (s), 22.8(s), 23.1 (w), 23.8 (w, shoulder), 24.1 (s), 24.8 (s), 25.7 (m), 26.2(vw), 26.6 (m), 26.9 (w), 28.4 (w), 29.5 (w), 29.8 (vw), 30.9 (m);wherein, for each of said polymorphs, (vs) stands for very strongintensity; (s) stands for strong intensity; (m) stands for mediumintensity; (w) stands for weak intensity; (vw) stands for very weakintensity.
 40. A crystalline polymorph A, B, C, D, E, F, or theamorphous form, of(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptanoicacid hemicalcium salt of claim 39, wherein polymorph A has an X-raypowder diffraction pattern substantially as depicted in FIG. 1,polymorph B has an X-ray powder diffraction pattern substantially asdepicted in FIG. 2, polymorph C has an X-ray powder diffraction patternsubstantially as depicted in FIGS. 3A and 3B, polymorph D has an X-raypowder diffraction pattern substantially as depicted in FIG. 4,polymorph E has an X-ray powder diffraction pattern substantially asdepicted in FIG. 5, polymorph F has an X-ray powder diffraction patternsubstantially as depicted in FIG. 6, and the amorphous form has an X-raypowder diffraction pattern substantially as depicted in FIGS. 7A and 7B.